In the photodynamic therapy of cancer, certain dye compounds (eg, hematoporphyrin derivative, chloroaluminum phthalocyanine sulfonate) are administered to a tumor-bearing subject. To some extent these dye compounds are taken up by the tumor tissue and upon selective irradiation with the appropriate light source the tumor tissue is destroyed via the dye mediated photo-generation of toxic species such as single; oxygen,
A large number of phthalocyanine (Pc) derivatives have been proposed as potential photodynamic therapeutic (PDT) agents. Most biological studies on Pc compounds related to PDT have been conducted with water soluble sulfonated metallo-phthalocyanines (as reported by Rosenthal. I. Photochem Photobiol 53(6). 859-870. (1991). These compounds are generally obtained by sulfonation of the appropriate metallo-phthalocyanine or by template synthesis using the appropriate sulfonated precursors and a metal salt. Both template synthesis and direct sulfonation results in mixtures of Pc's containing a variety of isomers and/or different degrees of sulfonation. This is a particular disadvantage with respect to pharmaceutical applications in that drug regulatory agencies are increasingly stringent in their requirements for substantially pure compounds.
Metallated Pc's have been found to have superior photosensitizing activity compared to metal-free Pc's when the metal is a main group element having a filled d shell (eg. Al. Zn, Sn. In). It has been reported by Chan, W S. et al. Photothem Photobiol. 45, 757-761 (1987), that transition metal complexes of Pc's have been found to be inactive (eg. Cu, Co, Ni. VO, Pal).
There remains a need for novel photosensitizers which can be prepared in isomerically pure form and which show a good level of activity.
The present invention provides novel transition metal phthalocyanine-type derivatives of formula I. ##STR2## wherein M is a second or third row transition metal with a d.sup.6 low-spin electronic configuration,
X is hydrogen, alkyl, alkoxy, halide or adjacent X's may together form --C.sub.4 H.sub.4 --, PA1 each R is a ligand selected from phosphine, mine, amine, isocyanide, nitrile, thiolate, hydrazine, cyanide, thiocyanate, phenolate, sulphide and analine groups having a water-solubilizing moiety, and PA1 Q is nitrogen or --CY--, where Y is hydrogen, alkyl, alkoxy or halide, in water-soluble salt or acid form.
Preferably. M is selected from Ru, Rh, Os or Ir. Suitable ligands R incorporate triphenylphosphine or triethylphosphine, and solubilizing groups are suitably sulfonate or carboxylate groups. When R incorporates an amine, it may be a straight or branched chain amine, or an aromatic amine such as pyridine. Preferred R ligands are triphenyl-phosphine mono-, di- or tri-sulfonate, 4-pyridine ethanesulfonate, 3-pyridine sulfonate, triphenylphosphine monocarboxylate, 4-isocyanobenzoate, nicotinic acid, taurine or amino acids.
Preferably, the compound is in salt form, with counterions which are desirably K.sup.+, Na.sup.+ or quaternary ammonium.
The compounds of formula I are novel, and may be prepared by a process comprising reacting a metal phthalocyanine compound of formula II, ##STR3## wherein M, Q and X are as define above, and A is an amine, preferably a pyridine group, CO (carbon monoxide) or a co-ordinating solvent, for example benzonitrile, with a salt of the ligand R, and isolating the product compound of formula I.
Many of the reactants of formula II, and the salts of ligand R, are known from the literature. However, compounds of formula II in which A is ammine, benzonitrile, methylcyanide or another co-ordinating solvent, are believed to be novel and form part of the present invention. Although such compounds may be prepared by methods analogous to those in the art, the invention further provides a method of producing said novel compounds of formula II in which A is benzonitrile by reacting M phthalocyanine bis(ammine) with benzonitrile. The ammine complex may be prepared by reacting MCl.sub.3. xH.sub.2 O, where x is 2 or 3, with phthalonitrile, and then with ammonia.
Suitably, the starting metal phthalocyanine or naphthalocyanine is mixed in an organic solvent, such as mixed xylenes, with an excess, for example 2-10 fold stoichiometric, of an organic-soluble form of the water solubilizing ligand, under an inert atmosphere, such as argon. The reaction is carried out desirably by heating, for example at reflux for about two days. The product may be isolated by the addition of a co-solvent to the reaction mixture. If required, the solubility of the product may be enhanced by exchanging the counterions, in generally known
It is believed that the present invention, by incorporating a water solubilizing axial ligand, instead of the conventional substitution at the periphery of the Pc to obtain water solubility, permits the synthesis of isomerically pure compounds. The novel compounds have been found to be active in in vitro and in vivo tests for photosensitizing activity described hereafter.
The present invention also provides a pharmaceutical composition comprising a compound of formula I in admixture or association with a pharmaceutically acceptable carrier or diluent. The invention is also considered to include a method of treatment of a mammal having a tumor susceptible to photodynamic treatment, wherein the mammal is administered an effective dose of a compound of formula I or a pharmaceutically acceptable salt form thereof, and the tumor is subjected to light radiation.
The pharmaceutical compositions may be formulated according to well-known principles, and may desirably be in the form of unit dosages determined in accordance with conventional pharmacological methods. The unit dosage forms may provide a daily dosage of active compound in a single dose or in a number of smaller doses- Dosage ranges may be established using conventional pharmacological methods and are expected to lie in the range 1 to 50 mg/kg of body weight. Other active compounds may be used in the compositions or administered separately or supplemental therapy may be included in a course of treatment for a patient. The pharmaceutical compositions may desirably be in the form of solutions or suspensions for injection, or in forms for topical application, including application in the oral cavity. Suitable carriers and diluents are well known in the art, and the compositions may include excipients and other components to provide easier or more effective administration.
Following administration to the patient, photodynamic therapy may be carried out in conventional manner, using light sources and delivery systems that are known in the art. See, for example, Phys Med Biol. (1986). 31. 4. 327-360.